Expert Consensus on Prevention and Treatment of COVID-19 Infection in Patients with Lung Cancer

Corona virus disease 2019 (COVID-19) infection has become a major public health issue affecting human health. The main goal of epidemic prevention and control at the current stage in China is to “protect people’s health and prevent severe cases”. Patients with lung cancer who receive antitumor therapy have low immunity, and the risk of severe illness and death once infected is much higher than healthy people, so they are vulnerable to COVID-19 infection. At present, less attention has been paid to the prevention and treatment of COVID-19 infection in patients with lung cancer in domestic guidelines and consensus. Based on the published data in China and abroad, we proposed recommendations and formed expert consensus on the vaccination of COVID-19, the use of neutralizing antibodies and small molecule antiviral drugs for patients with lung cancer, for physician’s reference.


Introduction
Lung cancer is a malignant tumor with high morbidity and mortality in China and other countries around the world.The 5-year survival rate is only 19% [1] .Since the rapid spread of Corona virus disease 2019 (COVID- 19) infection worldwide, it has become the third cause of death in the United States in 2021 [2] .Due to the old age of most patients with lung cancer, multiple underlying diseases, immunosuppression caused by the antitumor therapy, repeated visits to hospitals, and other factors, the risk of COVID-19 infection, severe illness, and death of patients with lung cancer is much higher than that of healthy people [3] .
Vaccination is still the main effective way to prevent COVID-19 infection and severe illness in patients with lung cancer.However, patients with cancer are often excluded from the clinical trials of vaccine development.The efficacy and safety of vaccination in patients with cancer remain to be studied, and it is unclear how to better play the synergistic effect of prevention and treatment.In addition, the immune function of patients with lung cancer is impaired, the effects of vaccine prevention and treatment need further obser vation.The goal of prevention and treatment of COVID-19 infection in patients with cancer and vaccination and immunization strategies need to be determined.Based on the clinical practice of COVID-19 infection in patients with lung cancer, considering the relevant data in China and abroad and China's epidemic prevention and control policies, the Non-small Cell Lung Cancer (NSCLC) Expert Committee of Chinese Society of Clinical Oncology (CSCO) and China Medical Education Association have formed the first expert consensus on prevention and treatment of COVID-19 infection in patients with lung cancer after extensive consultation.
The principles of expert recommendation and evidence rating in this consensus are as follows: R ecom mend at ion level: A= st rong; B =moderate; C=optional.Evidence level: I=1 or more randomized t r ia ls w it hout sig n i f ica nt l i m itat ions; I Ia=ot her randomized trials or subgroup analyses of randomized trials; IIb=non-randomized trials or observational cohort studies; III=expert opinion. of vulnerable people, unbalanced regional development, and insufficient medical resources.Affected by virus mutation, spring and winter climate, and prevention and control policy factors, how to ensure the safety of people at high risk of COVID-19 infection is a key and decisive factor in achieving the goal of "protecting people's health and preventing severe cases".

Current status of COVID-19 infection in patients with lung cancer
It is estimated that about 870,000 new cases of lung cancer are expected in China (excluding Taiwan province) in 2022, accounting for 18.07% of the total number of new cancers, ranking first among malignant tumors in China [1] .The average age of lung patients is 70 years old [5] , and most of them are also suffering from smoking-related chronic air way and cardiovascular diseases, etc. Coupled with surgery, chemotherapy, radiotherapy, patients' immunity is weakened.Compared w ith the general population, patients with lung cancer have a higher risk of COVID-19 infection and a higher proportion of severe illness and death.A retrospective case-control study in the United States showed that patients with newly diagnosed lung cancer had a significantly increased risk of COVID-19 infection [odds ratio (OR)=7.66;95%CI: 7.07-8.29;P<0.001] [6] .A retrospective analysis in China showed that lung cancer accounted for the highest proportion of patients with cancer infected with COVID-19, at 20.9% (22/105) [7] .In 2022, a meta-analysis of 21,257 patients with lung cancer who were infected with COVID-19 showed that the mortality rate of patients with lung cancer was significantly higher than that of patients without cancer [hazard ratio (HR)=2.00;95%CI: 1.52-2.63;P<0.01], and also higher than that of patients with other tumors (HR=1.91;95%CI: 1.53-2.39;P<0.01) [7] .A retrospective analysis in the United States in 2020 showed that 62% of patients with lung cancer who were infected with COVID-19 required hospitalization, 40% required intensive care unit (ICU) treatment, and the mortality rate was as high as 25% [8] .Domestic g uidelines and consensus recommended t hat pat ients w it h ma l ig na nt t u mors shou ld receive COVID-19 vaccines.The safety of patients with cancer receiving COVID-19 vaccines is comparable to that of the general healthy population [9,10] .Patients with cancer can be vaccinated against COVID-19, but the immune response and protective effect are lower, according to the "Technical guidelines for vaccination of COVID-19 (version 1)".Patients with advanced cancer are not advised to receive COVID-19 vaccines [9] .According to "The Chinese expert consensus on issues related to the protection, treatment and management of patients with solid tumors during COVID-19", the type and degree of common adverse reactions of COVID-19 vaccination in patients with cancer are similar to those in healthy people, mainly manifested as injection site pain, fatigue, fever, chills, headache and myalgia [10] .

COVID-19 vaccination in patients with
COVID-19 vaccination in patients with lung cancer can increase the concentration of neutralizing antibodies and reduce the risk of severe infection, and the vaccination is safe.A cohort study of 201 patients with cancer (including 102 patients with lung cancer) showed that the seropositive rate of receptor binding domain (RBD) immunoglobulin G (IgG) in patients with cancer was 81.6% after receiving 2 doses of inactivated vaccines from Sinovac (CoronaVac), no grade 3 or above adverse reactions occurred [11] .A n observational study of 364 patients with cancer showed that 239 patients (86.9%) were seropositive after 2 doses of inactivated vaccines from Beijing Institute of Biological Products Co. Ltd (BBIBP-CorV); in terms of the safety, pain at the injection site and fever were the most common adverse reactions [12] .A total of 719,735 patients were enrolled in the large cohort study in Colombia, of which 9,308 were patients with cancer.The results showed that vaccination with 2 doses of inactivated vaccines from Sinovac could reduce the hospitalization rate of COVID-19 infection (33.1%; 95%CI: 14.5-47.7),admission rate of severe illness (47.2%; 95%CI: 18.5-65.8),and mortality rate (55.7%; 95%CI: 32.5-70.0) [13].The above results indicated that COVID-19 vaccination has a protective effect on patients with lung cancer, and the vaccination is safe.After the full immunization, the booster immunization can increase the protective effect on patients with cancer and reduce the COVID-19 infection rate, hospitalization 中国肺癌杂志 www.lungca.orgrate, and mortality rate.In a retrospective study of 2,578 patients with cancer (including 325 with NSCLC), patients with cancer who received booster immunization (2 doses of inactivated vaccines from Sinovac + 1 dose of BNT162b2 + 3 doses of inactivated vaccines from Sinovac) had a lower rate of COVID-19 infection compared with patients who did not receive booster immunization (83.7% vs 16.3%; P=0.000) [14] .A prospective study of 346 patients with breast cancer, 296 with NSCLC, and 32 with small cell lung cancer showed that the third dose of BNT162b2 vaccine (156 patients) significantly reduced the risk of hospitalization or death in patients with breast cancer compared with those without the vaccines (48 patients) (OR=0.30;95%CI: 0.15-0.57;P=0.01), while there were no significant changes in patients without the third dose of the vaccine (133 patients) (OR=0.64;95%CI: 0.3-1.24;P=0.19) [15] .A multicenter study of 97 patients with solid tumors (including 12 with NSCLC) and 82 healthy participants who received 2 doses of the vaccines but were seronegative showed a seropositive rate of approximately 30% in patients with solid tumors (71% in the healthy participants) after the third dose of inactivated vaccines from Sinovac, indicating that 3 doses of the vaccines had protective effect in patients with solid tumors [16] .Results of a cohort study showed that the serological response of 216 patients with solid tumors (lung cancer: 23.4%) was assessed after the third dose of BNT162b2 vaccine, compared with the first month after the vaccination, the antibody titer of patients with solid tumors decreased by 1.94-fold at 4 months after the vaccination (1,239.63AU/mL vs 639.42 AU/mL).The estimated half-life of serum IgG in patients with solid tumors was 88 days, and the time for serum antibody to turn negative was 588 days, indicating that patients with cancer needed to receive a second dose of booster immunization [17] .

Booster immunization with COVID-19 vaccines in patients with lung cancer
Several domestic and foreign guidelines recommended booster immunization for patients with malignant tumors.According to "The Chinese expert consensus on issues related to the protection, treatment and management of patients with solid tumors during COVID-19 (2022 edition)", patients with cancer should receive the recommended dose and complete the recommended number of doses [10] .According to the United States National Comprehensive Cancer Network (NCCN), most patients with cancer (except those in the perioperative period of major surgery) should complete the full vaccination and the second booster vaccination as early as possible [18] .
According to China's "Work plan for strengthening the vaccination of the elderly against COVID-19", the interval between the first dose of booster immunization and the full vaccination should be adjusted to more than 3 months, based on the data from real world studies and clinical trials in China and abroad, as well as the actual vaccination of the elderly population in China [19] .Therefore, it is recommended that patients with cancer should complete the first booster vaccination at 3 months after the full vaccination.
As for the second booster vaccination, according to China's "Notice on issuing the implementation plan for the second booster vaccination of COVID-19", on the basis of the first booster vaccination, the second booster vaccination should be administered in people at high risk of infection, elderly people over 60 years of age, people with more serious underlying diseases, and people with low immunity (including patients with cancer) [20] .According to the actual vaccination practice in China, the interval between the second dose and the first dose of booster vaccination should be more than 6 months.Therefore, it is recommended that patients with cancer should complete a second booster vaccination 6 months after the first booster vaccination.

Vaccination of patients with lung cancer after previous COVID-19 infection Consensus 3: Patients w ith lung cancer who have p r e v i o u s l y b e e n i n f e c t e d w i t h C O V I D -19 a r e recommended to receive the vaccine after 6 months of recovery (Recommendation level: B; Evidence level: IIb).
On 2 0 December 2 022 , t he Joi nt Prevent ion a nd Control Mechanism of the State Council stated at the press conference on medical services for key populations that, if it was confirmed by nucleic acid test or antigen test that the patient had recently been infected with COVID-19, the risk of re-infection within 3 to 6 months was low, and it was not recommended to vaccinate the infected people in a short period of time.According to the current vaccination recommendations, the vaccine can be given 6 months after COVID-19 infection.
The mixed immune response produced by the infection and vaccination is superior to that produced by the infection alone or vaccination alone [21] .A cohort study in 2021 included 63 former COVID-19 patients, 41% of whom were vaccinated against COVID-19.The results showed that RBD antibody reactivity, neutralizing activity, and the number of RBD-specific memory B cells in unvaccinated recovered patients remained relatively stable between 6 and 12 months after the infection, while the antibody neutralizing activity in vaccinated recovered patients was further improved by about 50-fold [22] .Patients with cancer with impaired immune function are still at the risk of being re-infected with COVID-19.It is recommended that patients with lung cancer should be actively vaccinated 6 months after recovery.Patients undergoing lung cancer surgery are a priority group for COVID-19 vaccination.A study evaluated the population in priority for vaccination through modeling.The study was stratified by whether they underwent surgery (general population, cancer surgery, non-cancer surgery) and age (18-49 years, 50-69 years, ≥70 years), with the primary endpoint being the number needed to vaccinate (NNV) to prevent 1 death caused by COVID-19 infection within 1 year.The results showed that patients aged ≥70 years requiring cancer surgery had the greatest benefit from vaccination compared with the general population [NN V of 1,840 (1,196-3,066)], with NNV of 351 (196-816).Preoperative vaccination of patients requiring elective surgery over the general population could prevent an additional 58,687 (20,177-115,007) deaths related to COVID-19 infection within 1 year [23] .

COVID-19 vaccination in patients with
Vaccination against COV ID-19 may lead to adverse reactions such as fever.To accurately distinguish vaccinerelated adverse reactions from surgical complications, it is recommended that the vaccination should be more than 2 weeks apart from the date of surgery.The antibody response rate of patients with lung cancer vaccinated during the chemotherapy is lower and the protective efficacy of the vaccine decreases.A study of 201 patients with cancer (102 of whom had lung cancer) and 97 non-cancer patients showed that the antibody response to the vaccine was lower in patients w ith cancer who were receiving chemotherapy after 2 doses of inactivated vaccines from Sinovac (OR=0.303;95%CI: 0.123-0.750;P=0.010) [11] .A study of 776 patients with cancer (23.6% of whom had lung cancer) and 715 non-cancer patients showed that seropositive rates were significantly lower in the chemotherapeutic group than in the non-chemotherapeutic group after receiving inactivated vaccines from Sinovac (78.6% vs 91.1%; P<0.001) [24] .In addition, a meta-analysis of 39 studies, including 11,075 patients with cancer, showed that serum response was significantly lower in patients treated with antitumor therapy than in the untreated group (OR=2.55;95%CI: 2.04-3.18),and the seroconversion rate of patients with chemotherapy was lower than that of the group without chemotherapy (OR=3.04;95%CI: 2.28-4.05) [25].

COV ID-19 vaccination during radiotherapy/ chemotherapy
The Joint Prevention and Control Mechanism of the State Council stated in the "Work plan for strengthening the vaccination of the elderly against COVID-19" that patients with severe chronic diseases that are in the acute stage, such as patients with cancer undergoing chemotherapy, should postpone the vaccination [19] .According to "Expert advice on novel coronavirus vaccination in patients with malignant tumors", patients undergoing chemotherapy are not advised to receive COVID-19 vaccines, while those who have completed radiotherapy and chemotherapy for more than 1 month are advised to receive COVID-19 vaccines [26] .According to "The Chinese expert consensus on issues related to the protection, treatment and management of patients with solid tumors during COVID-19", patients with cancer should be vaccinated at least 2 weeks before chemotherapy or 1 to 2 weeks after the chemotherapy [10] .
No large sample clinical studies have been conducted to investigate the safety and efficacy of COVID-19 vaccines in patients with lung cancer receiving radiotherapy.A case report showed that an NSCLC patient who received 2 doses of COVID-19 vaccines during the radiotherapy developed acute radiation pneumonia [27] .Due to insufficient data on the safety of vaccination during the radiotherapy, it is recommended to postpone the vaccination during the radiotherapy.According to "The Chinese ex pert consensus on issues related to the protection, treatment and management of patients with solid tumors during COVID-19", in the absence of sufficient clinical data at this stage, patients with short-course radiotherapy can be vaccinated after the course of treatment, or at any stage of radiotherapy, taking into account the risk of COVID-19 infection and the patient's willingness [10] .According to "Expert advice on novel coronavirus vaccination in patients with malignant tumors", it is not recommended for patients undergoing radiotherapy, but can be vaccinated against COVID-19 after the radiotherapy [26] .

COVID-19 vaccination during immune checkpoint inhibitors (ICIs) therapy Consensus 6: During the treatment of ICIs, a thorough evaluated should be made, and patients should be vaccination with caution (Recommendation level: B; Evidence level: III).
Several studies showed that COV ID-19 vaccination to patients with cancer who are receiving ICIs is safe in the short term, but the long-term safety needs further assessment.A study of 454 patients with cancer (including 157 with NSCLC) showed that receiving programmed cell death 1 (PD-1) inhibitors did not affect the serological 中国肺癌杂志 www.lungca.orgresponse after the vaccination with inactivated vaccines (68.1% vs 71.3%) [28] .A real-world study of 2,048 patients with cancer (including 722 with lung cancer) receiving PD-1 inhibitors showed that compared with the unvaccinated group (530 patients), the group vaccinated with inactivated vaccines from Beijing Institute of Biological Products Co. Ltd (1,518 patients) neither increased the serious adverse reactions of PD-1 inhibitors nor reduced the efficacy of PD-1 inhibitors [29] .A meta-analysis of 39 studies involving 11,075 patients with cancer showed that the serological response of patients with cancer receiving immunotherapy (mainly including chimeric antigen receptor T cell therapy and ICIs) had no statistically significant difference compared with untreated patients (OR=1.23;95%CI: 0.85-1.76;P=0.27), suggesting that the use of ICIs may not affect the protective effect of COVID-19 vaccines [25] .
Lymphopenia, T cell depletion caused by high checkpoint expression, and inflammatory cytokine storm are the three most important immunological manifestations associated with poor outcome of COV ID-19.However, ICIs may potentially reactivate the depleted T cells, thus aggravating the inflammatory cytokine storm caused by COVID-19 and leading to organ damage [30] .According to "Expert advice on novel coronavirus vaccination in patients with malignant tumors", vaccination is not recommended for patients undergoing immunotherapy, as there is a risk of an overstrong immune response after vaccination, leading to or aggravating immune-related adverse reactions [26] .
Therefore, COVID-19 vaccination during ICIs treatment shou ld be considered w it h caut ion a f ter a t horough assessment, weighing the risks against the benefits.p o p u l a t i o n , w h o s e i m m u n e r e s p o n s e r a t e a n  Even if patients with lung cancer are vaccinated, their immune response and neutralizing antibody titers are lower than those of the general healthy population.They are still at high risk of COVID-19 infection.A real-world retrospective study with the largest sample size of COVID-19 infection cases and control group cases to date conducted in the United States showed that the risk of breakthrough infection in patients with solid tumors was 1.12-folder higher than that of non-cancer patients even after full vaccination (OR=1.12;95%CI: 1.01-1.23);the severity rate was 1.33-fold higher than that of non-cancer patients (OR=1.33;95%CI: 1.09-1.62) [31].

P re vent ion of COV I D -19 u s i n g lon g-ac t i n g neutralizing antibodies in patients with
In addition, the antibody titers were significantly lower in patients with lung cancer than in general healthy population after the vaccination.A study [32] assessing the antibody response of 82 patients w ith NSCLC and 53 healthy participants after receiving the mRNA booster (the third shot) showed that the neutralizing antibody titer in patients with NSCLC at 1 month after 2 doses of mRNA vaccines was 7 times lower than those in healthy participants (P≤0.0001);2-4 months after the third dose of the booster injection, the neutralizing antibody titer of the original and Omicron strains decreased by 5 and 7 times, respectively.During the active antitumor therapy, the immune function of patients with lung cancer decreases and the protective effect of vaccine decreases.The protective effect of COV ID-19 vaccine significantly reduces during the radiotherapy/chemotherapy in patients with cancer.A cohort study in United Kingdom of 230,666 patients with cancer who had received 3 doses of COVID-19 vaccines showed an increase in both breakthrough and symptomatic rates of infection in patients who received systemic antitumor therapy or radiotherapy within 1 year, compared with those who did not [33] .Another study including 201 patients with cancer (99 with breast cancer, 102 with lung cancer) and 97 non-cancer patients who had completed 2 doses of vaccines showed that patients w ith cancer who were receiv ing active chemotherapy had lower antibody responses to the vaccines (OR=0.303;95%CI: 0.123-0.750;P=0.010) [11] .In addition, there are also some patients with lung cancer in China have never received COVID-19 vaccines.Therefore, it is particularly necessary to use neutralizing antibodies as passive immune protection for patients with lung cancer who are undergoing radiotherapy/chemotherapy.
Monoclonal antibody drugs designed for COVID-19 can specifically bind to viral particles and have neutralizing capabilities, thus helping to clear and reduce the viral load in the body.Therefore, neutralizing antibodies can provide susceptible individuals with antibodies that cannot be produced by the body itself to neutralize the virus, offering hope for patients with lung cancer to prevent COVID-19 infection.Patients with suppressed immune function (eg, patients with solid and hematological tumors, patients with primary and acquired immunodeficiency, and patients with 中国肺癌杂志 www.lungca.orgsolid organ and hematopoietic stem cell transplantation) may be passively immunized with long-acting neutralizing antibodies to achieve a higher level of immune protection.Tixagevimab/Cilgavimab is the only drug approved in the world for both prevention and treatment of COVID-19.It is a cocktail of neutralizing antibodies targeting 2 different regions of the spike protein of the virus, enhancing the ability to neutralize the virus and new mutant strains [34] .The PROVENT study, a phase III clinical study of Tixagevimab/ Cilgavimab, included 5,197 adults worldwide who had an inadequate response to the vaccine or were at high risk of COV ID-19 infection, 7.7% of whom had malignant tumors and were randomized to receive either a single dose of Tixagevimab/Cilgavimab (n=3,460) or placebo (n=1,737).The results showed that Tixagevimab/Cilgavimab significantly reduced the relative risk of symptomatic COVID-19 infection by 83% (P<0.001), with a protective effect of ≥6 months [35] .In terms of safety, most of the adverse event within 15 months after a single dose were mild or moderate and comparable to those in the placebo group.
I n M a rc h 2 0 2 2 , t he E u r o p e a n Un i o n a p pr o v e d Tixagevimab/Cilgavimab for the pre-exposure prophylaxis against COV I D-19 in adults and adolescents over 12 years of age (body weight >40 kg).On 8 December 2021, the Food and Drug Administration (FDA) approved the Emergency Use Authorization for Tixagevimab/Cilgavimab as a pre-exposure prophylaxis measure for moderately to severely immunocompromised patients or patients who do not receive COVID-19 vaccines due to a history of severe adverse reactions [40] .The recommended dose is 300 mg of Tixagevimab and 300 mg of Cilgavimab administered by continuous intramuscular injection, and repeated every 6 months to ensure lasting protective effect.
The United States NCCN guidelines recommended that immunocompromised patients with cancer, including those receiving antitumor therapy, were prioritized for the use of long-acting neutralizing antibody of Tixagevimab/ Cilgavimab, as a preventive measure against COVID-19.The vaccine can be administered immediately after the administration of Tixagevimab/Cilgavimab.For those who receive the vaccine first, it is recommended to use Tixagevimab/Cilgavimab 2 weeks later to avoid affecting the vaccine-induced immune response.Tixagevimab/ Cilgavimab is not a substitute for COVID-19 vaccine [41] .

The use of neutralizing antibody after the recovery from COVID-19 infection in patients with lung cancer Consensus 8: Patients w ith lung cancer who have recovered from previous infection with COVID-19 can use long-acting neutralizing antibody (Tixagevimab/ Cilgavimab, 600 mg, intramuscularly) after 3 to 6 months of recovery to reduce the rate of COVID-19 re-infection and hospitalization (Recommendation level: B; Evidence level: IIb).
Given that the virus is constantly mutating, patients with lung cancer who have already been infected with COVID-19 are still at risk of being re-infected with the mutated strains.Clinical studies involving previously infected people showed that the use of neutralizing antibodies can reduce the risk of re-infection.In an Israeli retrospective analysis during 中国肺癌杂志 www.lungca.org the Omicrone epidemic, 5,124 immunocompromised patients over the age of 12 years were included, 825 patients receiving Tixagevimab/Cilgavimab tended to match 4,299 untreated patients, of whom 64% in the treatment group had cancer and 20.7% had previous COVID-19 infection.The results showed that compared with the untreated group, the Tixagevimab/Cilgavimab treatment group significantly reduced the risk of COVID-19 infection by 49% (3.5% vs 7.2%; P<0.001; OR=0.51; 95%CI: 0.30-0.84),hospitalization rate for COVID-19 infection (0.1% vs 0.6%; P=0.07) and death by 92% (0% vs 0.9%; P=0.005; OR=0.08; 95%CI: 0.01-0.54) [42].A retrospective cohort study in France included 1,112 immunocompromised patients who had received Tixagevimab/Cilgavimab, of whom 9.6% being previously infected with COVID-19.The results showed that Tixagevimab/Cilgavimab reduced the rate of COVID-19 related hospitalizations by 80.2% [43] .Neutralizing antibody levels rapidly decline in humans 3-6 months after COVID-19 infection, thus, it is recommended that patients with lung cancer should be treated with Tixagevimab/Cilgavimab at this time point.

Daily prevention of COVID-19 infection in patients with lung cancer
Consensus 9: It is recommended that patients with lung cancer should insist on wearing masks, washing hands frequently, maintaining social distance, and taking good personal protection (Recommendation level: A; Evidence level: I).

Precautions for daily protection of patients with lung cancer
Patients with lung cancer should maintain good personal and environmental hygiene, balanced nutrition, moderate exercise, adequate rest, and avoid excessive fatigue.Patients w ith lung cancer should improve health literac y and develop hygiene habits and lifestyles such as "one-meter line", frequent hand washing, wearing masks, and using serving chopsticks.Patients should keep the room well ventilated and have scientific personal protection.Patients with fever and respiratory symptoms should go to the clinic for medical treatment timely [44] .At the same time, family members and long-term caregivers of patients with lung cancer are advised to be vaccinated against COVID-19 to reduce the risk of transmission of the virus.The blood gas barrier is destroyed, the respiratory mucosal immunity and basic immune function of patients with lung cancer are impaired, and about 50% of patients with lung cancer are complicated with chronic obstructive pulmonary disease (COPD) [45,46] .For patients with COPD, it is recommended to use Staphylococcus and Neisseria tablets (also known as tracheitis Junmiao tablets, Qi tablets) and bacterial lysates to improve innate immunity and respirator y mucosal immunity, reduce repeated respiratory infections, and reduce the severity and frequency of acute exacerbation of COPD.Staphylococcus and Neisseria tablets are produced after the inactivation of three symbiotic human bacteria, including Staphylococcus albus, Neisserkatascus, and Bacillus subtilis, which are bacteria-derived immunomodulators which activate the non-specific immune system of the digestive tract after oral administration and produce specific antibodies (IgA) in the respiratory tract to enhance respiratory specific immune function [47][48][49] .Bacterial lysates are mainly lyophilized dissolved products of eight common respiratory tract infection bacteria.Clinical studies showed that the combination of bacterial lysates on the basis of conventional treatment can effectively reduce the number of acute exacerbations in patients with COPD, shorten the length of hospital stay and the duration of antibiotic use during the acute exacerbation of COPD, improve the clinical symptoms, and help to improve the lung function and immune function of patients [50][51][52] .Immunomodulators, such as thymalfasin, can enhance immune response to vaccines in patients with lung cancer with suppressed immune function.For patients with hypoxemia and lymphopenia caused by COVID-19 infection, conventional treatment combined with thymalfasin for 5 consecutive days can significantly increase CD4 + T cell count and accelerate clinical recovery with good safety [53] .

Diagnosis and treatment for patients with lung cancer
During the epidemic period, patients with lung cancer who have relatively stable diseases should minimize the number of visits to the hospital, and can choose the 24-hour online consultation service of regular hospitals to determine the appropriate time for review.For those who need surgical treatment, it is recommended to fully communicate with physicians, fully evaluate the patient's situation and surgical risks, to determine whether to undergo the surgery, or strengthen protection during surgery, to ensure surgical safety and avoid COV ID-19 infection.Patients in the antitumor treatment period have lower immune function and are more susceptible.Protective measures should be further strengthened.If the disease progresses rapidly or other abnormalities occur, patients should go to the hospital as early as possible [54] .Lung cancer is a high-risk factor for severe illness and death from COVID-19 infection.Antiviral therapy should be used early in patients with lung cancer after COVID-19 infection, which can rapidly reduce the viral load and reduce the risk of severe illness and death.Antiviral small molecule drugs approved in China include Nirmatrelvir tablets/Ritonavir tablets, Simnotrelvir tablets/Ritonavir tablets, Azvudine, Molnupiravir capsules, and Deuremidevir hydrobromide tablets; antibody drug include BRII-196/ BRII-198 monoclonal antibody.
During the anti-cancer treatment of patients with lung cancer, special attention should be paid to the interaction between chemotherapy drugs, targeted drugs, and antiviral drugs.Nirmatrelvir tablets/Ritonavir tablets should not be used with drugs that are highly dependent on CYP3A for clearance.The commonly used antitumor drugs and their interactions are shown in Table 1 [55] .For patients with lung cancer who have moderate kidney injury, the dosage of Nirmatrelvir tablets/Ritonavir tablets should be reduced.Nirmatrelvir tablets/Ritonavir tablets should not be used in patients with severe kidney injury or severe liver injury.
Compa red w it h a nt i v i r a l sm a l l mole c u le d r ug s , COVID-19 neutralizing antibodies have no limitation on liver and kidney function and no limitation of concomitant medications, and are safer.The decision to administer neutralizing antibodies needs to be made in conjunction with the neutralizing activity of the main circulating strain.In addition to the BRII-196/BRII-198 monoclonal antibody approved in China, Tixagevimab/Cilgavimab has also been approved in Europe and Japan for the treatment of mild to moderate COVID-19 infection in patients over 12 years of age (body weight> 40 kg) with high risk factors.The results of the TACKLE study, a phase III clinical study, showed that treatment with Tixagevimab/Cilgavimab 600 mg intramuscularly within 7 days after the onset of symptoms of COVID-19 infection significantly reduced the risk of severe illness or death within 29 days by 50.5% compared with the placebo group (4.4% vs 8.9%) [56] .R adiation/chemotherapy may reduce the immune responses in patients with lung cancer, and the time to clear the virus may be prolonged in patients with lung cancer, leading to longer duration of the disease and poor prognosis.ICIs may reactivate depleted T cells, thus aggravating the inf lammatory cytokine storm caused by COVID-19 and leading to organ damage.ICIs treatment can also cause adverse events such as immune pneumonia.If 3 kinds of diseases (immune pneumonia, lung cancer, and COVID-19) appear at the same time, clinical management will be difficult [57] .A large cohort study showed that recent chemotherapy treatment was identified as a predictor of severe COVID-19 infection, and the risk increased with the degree of myelosuppression (HR=17.31;95%CI: 6.52-45.98) [58].Real-world data suggested that chemotherapy in combination with ICIs may be harmful in patients with COVID-19 infection [59] .In addition, there is a potential drugdrug interactions between antiviral and antitumor agents, and patients on long-term oral targeted antitumor agents are at high risk for severe drug-drug interactions.The United States NCCN recommended that for severe and critically ill patients with cancer, antitumor therapy should be delayed for >20 days if conditions allow, or until symptoms improve; for mild and moderate cases, it is recommended to delay treatment for >14 days, or until symptoms improve [60] .According to a survey of Chinese experts, when NSCLC is complicated with COVID-19 infection, 95.95% of the experts believe that chemotherapy should be discontinued, 86.91% of the experts believe that targeted therapy should be discontinued for severe/critical COVID-19, and 95.95% of the experts believe that immunotherapy should be discontinued [61] .

Treatment of traditional Chinese medicine
COVID-19 belongs to the category of epidemic disease in traditional Chinese medicine.Because of the feeling of "epidemic rage", the disease can be treated according to the condition, syndrome, and climate.Qingfei Paidu decoction is suitable for mild, moderate, severe, and critical cases, and is used in accordance with the patient's condition.Available Chinese patent medicines include Huox iang Zhengqi capsules (soft capsules, pills, water, and oral liquid), Shufeng Jiedu capsules (granules), Qingfei Paidu granules, Huashi Baidu granules, Xuanfei Baidu granules, Sanhan Huashi granules, Jinhua Qinggan granules, and Lianhua Qingwen capsules (granules).

Management of patients with severe illness
Early identification of patients with severe illness is the key to the treatment of COVID-19.The National Health Commission issued the "Diagnosis and treatment for severe cases of COVID-19 infection (trial 4 th edition)", proposing that for those who do not meet the diagnostic criteria for severe cases but have pneumonia caused by COVID-19 中国肺癌杂志 www.lungca.orginfection and have one of the following conditions can also be treated as severe cases: age >65 years, incomplete vaccination, complicated chronic diseases (including hypertension, diabetes, coronary heart disease, chronic lung disease, malignant tumors, immunocompromised, etc.) [62] .Therefore, patients with lung cancer should be managed as severe cases after infection with COVID-19, and early and active intervention should be performed to monitor vital sign measurements, especially finger oxygen saturation at rest and after activity, in the meanwhile monitoring the relevant indicators of the underlying disease.According to the "Diagnosis and treatment for COVID-19 infection (trial 10 th edition)", the following changes should be alert to the deterioration of the disease: hypoxemia or progressive aggravation of respiratory distress; deterioration of tissue oxygenation indicators (eg, oxygen saturation, oxygenation index) or progressive increase of lactic acid; progressive decrease of peripheral blood ly mphocy te count or progressive increase of inf lammatory factors (eg, interleukin-6, C-reactive protein, ferritin); significant increase of coagulation function related indicators (eg, D-dimer); and significant progression of pulmonary lesions on chest imaging [63] .
In the treatment of severe cases, adequate energy and nutrition intake should be ensured, water and electrolyte ba l a nc e s hou ld be pa id at t e nt ion to, a nd i nt e r n a l environment stability should be maintained.Those with high fever can undergo physical cooling and apply antipyretic drugs.Patients with severe cough and expectoration should be given anti-tussive and expectorant drugs.Patients should avoid blind or inappropriate use of antibiotics, especially in combination with broad-spectrum antibiotics.Those with underlying diseases should be treated accordingly.The main treatment measures for severe cases in the "Diagnosis and treatment for severe cases of COVID-19 infection (trial 4 th edition)" include antiviral therapy, immunotherapy, anticoagulant therapy, prone position therapy, oxygen therapy and respiratory support, circulation monitoring and support, nutritional support therapy, analgesia and sedation, acute kidney injury and kidney replacement therapy, and traditional Chinese medicine treatment [62] .

Conclusion
The main goal of epidemic prevention and control at the present stage in China is to "protecting people's health and preventing severe cases".Lung cancer is the most common tumor in China, patients with lung cancer are at high risk of severe illness and death caused by COVID-19 infection.The prevention and treatment of COVID-19 infection in patients with lung cancer should be highly concerned.COVID-19 vaccine is one of the most important therapeutic means to combat the COVID-19 epidemic.Patients with lung cancer should complete the full immunization and the booster immunization as early as possible.In addition, patients with lung cancer are a vulnerable population and the immune response rate and neutralizing antibody titers of these patients after vaccination are lower than those of healthy people.Neutralizing antibodies (Tixagevimab/Cilgavimab) can reduce the risk of COVID-19 infection, severe illness, and death, and are an important addition to protect patients with lung cancer.As the virus continues to mutate and the future epidemic trend is unpredictable, physicians, disease control personnel, and patients should pay attention to the new variant strain in real time, and pay attention to the progress of the research and development of COVID-19   Table 1 Interactions between Nirmatrelvir tablets/Ritonavir tablets (Paxlovid ® ) and anticancer drugs [56] Anticancer drug Nirmatrelvir tablet/Ritonavir tablets Explanation

1 :
Patients w it h lu ng cancer, who a re susceptible to COV ID-19 and at high risk of severe illness and death from the virus, should be vaccinated with priority.It is recommended that patients should be fully assessed and encouraged to receive the full course of vaccination against COVID-19 as early as possible (Recommendation level: A; Evidence level: I).

Consensus 2 :
Patients w ith lung cancer who have completed the full immunization against COVID-19 are revised to receive the first booster immunization after an interval of 3 months; and the second booster immunization af ter an inter val of 6 months af ter the completion of the f irst booster immunization (Recommendation level: A; Evidence level: I).
lung cancer during antitumor therapy 3.3.1 COVID-19 vaccination during surgery Consensus 4: For patients with lung cancer requiring surgery, it is recommended that the vaccination date should be ±2 weeks from the surgery date.If the patient 中国肺癌杂志 www.lungca.orgreceives the COVID-19 vaccine and experiences vaccinerelated adverse reactions, surgery for the lung cancer should be considered after the vaccine-related adverse reactions completely resolve, except for emergency surgery (Recommendation level: C; Evidence level: III).

Consensus 5 :
During the radiotherapy/chemotherapy, the immune function decreases so that the protective efficacy of vaccine is decreased.Patients with lung cancer undergoing radiotherapy/chemotherapy are advised to postpone COV I D-19 vaccination.Patients who discontinue the radiotherapy/chemotherapy for more than 1 month are advised to receive COVID-19 vaccines (Recommendation level: B; Evidence level: IIb).

lung cancer 4 . 1
Prevent ion of COV I D -19 usi ng neut ra l izi ng antibodies in patients with lung cancer Consensus 7: Patients with lung cancer are vulnerable d neutralizing antibody titers after the vaccination are lower than those of the general healthy population.It is recommended that patients with lung cancer use long-acting neutralizing antibody against COVID-19 (Tixagevimab/Cilgavimab, 600 mg, intramuscularly, once ever y 6 months) as a means of pre-ex posure prevention to reduce the risk of COVID-19 infection, severe illness, and death.After the vaccination, it is recommended to use Tixagevimab/Cilgavimab after an interval of 2 weeks; after Tixagevimab/Cilgavimab injection, the vaccine can be administered without an interval (Recommendation level: B; Evidence level: I).

6
Treatment of COVID-19 infection in patients with lung cancer 6.1 Antiviral therapy Consensus 10: Patients with lung cancer who infected w ith COV I D -19 should use antiv iral dr ugs (such as antiv iral small molecule dr ugs and COV I D-19 中国肺癌杂志 www.lungca.orgneutralizing antibodies) as early as possible to reduce the risk of severe illness and death (Recommendation level: A; Evidence level: I).

Consensus 11 :
Patients with lung cancer who test positive for COVID-19 should consider to delay the antitumor treatment according to the severity of infection and tumor status; if the current condition is urgent and the tumor spread is uncontrolled, antitumor treatment is urgently needed, the severity of COVID-19 infection and the risk of tumor progression should be fully assessed, and the treatment should be continued under the guidance of professional physicians (Recommendation level: B; Evidence level: III).
Combination prohibited A) The combination of 2 drugs affects the efficacy of Paxlovid ® ; B) The combination of the 2 drugs leads to high drug concentration causing severe adverse events; C) Discontinue, consider resuming the administration 3 days after the use of Paxlovid ® .Vometinib Combination prohibited Gefitinib Obvious interaction, preferably switch or discontinue Discontinue or change to other alternative drugs.If necessary, pay close attention to the patient's symptoms and discontinue the drug in a timely manner.Erlotinib Obvious interaction, preferably switch or discontinue Afatinib Obvious interaction, preferably switch or discontinue Savolitinib Weak interaction, may be combined Only partially metabolized by CYP3A4, weak interaction, low risk of severe adverse events.No action required.Osimertinib Can be used in combination No interaction Alectinib Can be used in combination Pemetrexed Can be used in combination Dacotinib Can be used in combination 中国肺癌杂志 www.lungca.orgvaccines and drugs, to maximize the benefit of patients with lung cancer during the epidemic.